1:4-benzodioxan derivatives



United States Patent 3,277,090 1:4-BENZODIOXAN DERIVATIVES Burton K. Wasson, Valois, Quebec, and John M. Parker, Montreal, Quebec, Canada, assignors to Charles E. Frosst & Co., Montreal, Quebec, Canada, a corporation of Quebec No Drawing. Filed July 9, 1963, Ser. No. 293,886 Claims priority, application Great Britain, July 16, 1962, 27,288/ 62 22 Claims. (Cl. 260247.5)

This invention is concerned with the preparation of novel 1:4-benzodioxan derivatives of the general formula:

group through a carbon or nitrogen atom.

The compounds of the above general formula may be prepared in any of several desired ways. A suitable method is as follows:

lc4 benzodioxans of the general formula:

R: in which R R R and n having the above meanings, are condensed with a primary amine of the general formula NH (CH Z in which n and Z have the above mean- Patented Oct. 4, 1966 "ice ings. The condensation can take place by heating in the presence or absence of an inert solvent, however preferably the amine serves as the solvent vehicle. Isolation of the compounds so obtained is by distillation after the mixture has been made alkaline, or crystallization of the acid addition salts.

The compounds according to the invention are generally used in the form of their acid addition salts, preferable as the hydrochloride. They possess strong adrenolytic properties as shown by their blockade of epinephrine. In addition the compounds show central adrenergic blockade in their ability to block parachlorophenylethylamine and mescaline.

These drugs are of value for use in the psychiatric treatment of excitation states and should also prove useful in the treatment of amphetamine poisoning.

As can be seen from the following rsum, the compound 2-(3-pyridylmethylaminomethyl)-1,4-benzodioxan was tested in mice, rats, cats and dogs with the noted results:

TABLE I Mice:

Acute toxicity, LD mg./kg., I.P. 310 Paralytic dose, PD mg./kg., LP. 170 Audiogenic seizure reduction, mg./kg. 50

Amphetamine excitement blockade, mg./kg.,

I.P. 12.5 Rats: Parachlorophenylethylamine blockade,

mg./kg., I.P. 50 Cats:

Parachlorophenylethylamine and mescaline blockade, mg./kg., I.P 25 Adrenaline blockade, mg./kg., I.V 5 Dogs: Epinephrine and nor-epinephrine pressor responses blockade for 8 hours (blood pressure slightly lowered) mg./kg., orally 100 Epinephrine and nor-epinephrine pressor responses blockade for 4 hours mg./kg., orally 25 Further pharmacological testing on some of the compounds of the invention is shown in Table II.

TABLE H.COMPARATIVE TEST RESULTS Cpd. Code Reserpine Reversal Adrenergic Blocking Test LDmPDm ED Spontaneous K6 Antagonism Test. Activity Test W327 ED50=7.3 rug/kg. CatB10cked 1 mgJkg. LD50=310 mgJkg. ED5u=1s mg./kg. Rat-50 nag/kg.

Reversed 2 mgJkg. P13502170 rug/kg. Blocked 15+30 m.

Depressed +120 m. CatB ocked 25 mg./kg.

W353 ED =12.5 mg./kg. Cat-Blocked 2 t0 4 IngJkg. LD50=490 mgJkg. Rat-50 mgJkg.

Reversed 16 rug/kg. PD50=270 mgJkg. Blocked 15, 30, 60, 120.

Cat-Blocked 25 mg./kg.

. '4 ED =17.5 n1 CatBlocked 4 mgJkg. LD50=205 mg./kg. Rat-50 rug/kg. W 33 50 g [kg PD =114 rug/kg. Blocked 15, 60 m.

Depressed 30 m. CatB1ocked 25 mgJkg.

W358 ED5D=3.3 mgJkg. Cat-Blocked 4 mgJkg. LD50=325 mg./kg. ED5D=11 mgJkg. RatmgJkg.

Reversed 8 mgJkg. PD5 =161 mg./kg. Blocked 15 m.

Depressed 30, 60. Cat-Blocked 25 rug/kg.

W359 ED5o=5A mg./kg. Cat-Blocked 1 to 2 mgJkg. LD50=580 mgJkg. ED5n=l8 mgJkg. Rat50 mgjkg.

Reversed 4 mgJkg. PD50=250 rug/kg. Blocked 15, 30 m.

Depressed 60. CatBlocked 25 mg./kg.

. 4 ED =40 m LD5=210 mgJkg. Rat-200 mgJkg. W 36 g [kg Blocked 15, 30, 60.

Cat -Depressed at 50 mgjkg.

W366 ED5n=52 mgJkg. Not blocked at 16 IngJkg. LD50=176 mg.[kg. Rat100 mgJkg.

Blocked 15, 30. Cat-Depressed 50 mg./kg.

ED =59 m LD5u=340 mgJkg, Rat-100 mg./kg. W 379 50 g [kg Blocked 15, 30, 60, m.

CatBl0eked 12.5 mg./kg.,

partially.

See footnotes at end of table.

TABLE II.COMPARATIVE TEST RESULTSContinued Cpd. Code Reserpine Reversal Adrenergic Blocking Test LD PD EDu Spontaneous K6 Antagonism Test Activity Test W380 ED5 =5 mg./kg. LD5u=178 mgJkg. ED |=36 mg./kg. Rat-50 mgJkg.

Blocked 15, 30, 60+120. Cat-Depressed mgJkg.

W381 ED5u=5A rug/kg. LD5u=360 mgJkg. Rat-100 mgJkg.

Blocked 15, a0, 60, 120 m. CatmgJkg.

Depressed 15, 30, m.

Conn: W327?Zg-pyridylmethylaminomethyl)-1,4-benzodioxan dihydro e on e. W353i? Z-(ii pyridylmethylaminomethyl)-1,4-benzodioxan dihydroc Oil e. W353?2 (2-pyridylmethylaminomethyl)1,4-benzodioxan dihydro- EXAMPLE I Preparation of 2-(2-pyridylamino)methyl-1,4-benzodioxan having the structural formula:

CHr-NH i A mixture of 36.9 grams (0.2 mole) of 2-chloromethyl- 1,4-benzodioxan and 38 grams (0.4 mole) of 2-aminopyridine was heated 31 hours in an oil bath maintained at 130-145 C. The mixture was left overnight at room temperature with formation of large crystals. The mix ture was extracted with ethyl ether in the presence of 20 grams of sodium hydroxide dissolved in 300 ml. of Water. The solids were collected, washed with water and dried to give 29.5 grams of crude product melting at 253260 C. The ethereal layer was evaporated and the residue distilled to give a 13.7 gram recovery of 2-aminopyridine and 17 grams of residue. This residue was dissolved in methanol and treated with 6 N hydrochloric acid to give 7 grams of product melting at 255258 C. The total crude yield of 2-(2-pyridylamino)rnethyl-1,4-benzodioxan was 36.5 grams of theory). Recrystallization of the crude products from methanol afiorded an analytical sample of the monohydrochloride melting at 265267 C.

A lZGlySl S.C3.lCd. C14H 5ClN2O I N, 10.05. Found: N, 9.96.

Similarly, condensation of 2-chloromethyl-l,4-benzodioxan with mand p-aminopyridine would give 2-(3- pyridylaminomethyl) -and 2-(4-pyridylaminomethyl) -1,4- benzodioxans. Similarly, condensation of 2-chloromethyl-8-methoxy-1,4-benzodioxan with 0-, mand p-aminopyridine would give 2-(2-pyridylaminomethyl)-S-methoxy-1,4-benzodioxan and the 3- and 4-pyridylaminomethyl isomers.

EXAMPLE H Preparation of 2-(3-pyridylmethylaminomethyl)-1,4 benzodioxan having the structural formula:

A mixture of 124.2 grams (0.67 mole) of 2-chloromethyl-1,4-benzodioxan and 145.5 grams (1.35 moles) of 3-picolylamine was heated seven hours in a glascol with the internal temperature being maintained at 115-121 C. The gummy solid which formed during the reaction was broken up in order to maintain efficient stirring. The reddish-brown mixture was left overnight at room temperature. The semisolid was dissolved by warming with W366=2(3)-(3-pyridylmethylaminomethyl)-5-rnethyl-8-isopropyl-l,4-

benzo ioxan. W.379 =2-( -(N-morpholino) propylaminomethyl)-6(7)-ehloro-1,4-bcnzo- W.380 2 l 3 -(v-(N-rnorpholino)propylaminomethyl)-5-methyl-8-isopro pyl-1,4-benzodioxan. W.381=2-('y-(N-morpholino)propylaminomethyl)-6(7)-methyl-1,4 benzodioxan. su=Efiective dose 50%. 5o=Lethal dose 50%. so Spout. Act. Test=Amphetamine excitement blockade. K6 Test=Parachlorophenylethylarnine and mescaline blockade.

water on the steam-bath. The cold aqueous solution was covered with a layer of ethyl ether and 230 mls. of con centrated hydrochloric acid was added dropwise. The aqueous portion was further extracted with ethyl ether, and the combined ethereal extracts were evaporated to give a recovery of 24.7 grams of 2 chloromethyl 1,4- benzodioxan. The aqueous layer was made basic by the addition of 160 grams of sodium hydroxide dissolved in 300 mls. of water. The mixture was extracted with ethyl ether, the combined ethereal extracts washed with water and the solvent evaporated to give 103.6 grams of residue. Distillation of this residue removed 15.2 grams of 3-1 picolylamine. The residue was dissolved in mls. of 6 N hydrochloric acid and the solution evaporated to dryness. The solid was dissolved in methanol, treated with charcoal, filtered, the filtrate concentrated, diluted with ethyl ether, cooled and the crystalline product collected. The total purified yield of 2-(3-pyridylmethylaminomethyl)-1,4-benzodioxan dihydrochloride was 100.5 grams (45.4% of theory) melting at 167177 C. The analytical sample was obtained by repeated recrystallization from methanol-ethyl ether without an improvement in the melting point.

Analysis.Calcd. for C15H1gCl2N202: C, H, 5.51; N, 8.51. Found: C, 54.92; H, 5.70; N, 8.16.

Condensation of 2-chloromethyl-1,4-benzodioxan with o-, m-, p-aminoethylpyridine and o-, mand p-aminopropylpyridine would give 2- (2-pyridylethylaminomethyl 2- 3-pyridylethylaminomethyl) 2- 4-pyn'dylethylaminomethyl) 2- 2-pyridylpropylaminomethyl) 2-( 3-pyridylpropylaminomethyl and 2-(4-pyridylpropylaminomethyl) -1,4-benzodioxans respectively.

wherein the alkyl grouping is CH (CH (CH-Q (CH2); and (CH Similarly condensation of 2-chloromethyl-1,4-benzodioxan with 2- and 3-aminoalkylpyrroles would give the corresponding 2-(2-pyrrylalkylaminomethyl)- and 2-(3-pyrrylalkylaminomethyl)-1,4-benzodioxans wherein the alkyl group consists of one to five Similarly condensation of 2-chloromethylene groups. methyl-1,4-benzodioxan with 2- and 3-aminoa1kyl-1- methyl-pyrrolidines would give the corresponding 2-(1- methyl 2 pyrrolidinylalkylaminomethyl) and 2 (1- methyl 3 pyrrolidinylalkylaminomethyl) 1,4 ben- 2-(4-pyridylmethylaminomethyl) -1,4-benzdi0xan l @0 CH NHCH In the same manner as set forth in Example II, a mixture of 9.23 g. of 2-chloromethyl-1,4-benzodioxan and 16.2 g. of 4-aminomethylpyridine was heated six times at 115118 C. and left overnight at room temperature. Distillation of the crude product gave 3.7 g. of 2-(4- pyridylmethylaminomethyl) 1,4 benzodioxan boiling at l56160 C./0.0l5 mm., n 1. 5826. Treatment of the base with dilute hydrochloric acid gave 2-(4-pyridylmethylaminomethyl)-1,4-benzodioxan dihydrochloride as a white crystalline solid melting at 188192 C.

Analysis.Calcd. for C H N 0 -2HCl: C, 54.72%; H, 5.51%; N, 8.51%. Found: C, 54.91%; H, 5.61%; N, 8.53%.

EXAMPLE IV 2-(Z-pyridylmethylaminomethyl) -1,4-benz0di0xan In the same manner as set forth in Example H, a mixture of 9.23 g. of 2-chloromethyl-1,4-benzodioxan and 16.2 g. of 2-picolylamine was heated 6 hours at 114.0- 116.5 C. and left at room temperature overnight. The crude product was distilled to give 9.9 g. (77.3%) of 2- (2 pyridylmethylaminomethyl)-1,4-benzodioxan boiling at 155.0156.5 C./0.030.04 mm. pressure, n 1.5772. Treatment of the base with 6 N HCl, followed by evaporation in vacuo, drying and recrystallization from methanol-ether gave 11.5 g. of 2-(2-pyridylmethylaminomethyl)-1,4-benzodioxan dihydrochloride as a white powder melting at 165-170" C. (decomposition). Despite many recrystallizations, the melting point remained wide.

Analysis. Calculated for C H N O 2HCl: C, 54.72%; H, 5.51%; N, 8.51%. Found: C, 55.06%; H, 5.42%; N, 8.44%.

EXAMPLE V 2-(2-(6-methylpyridyl)methylamin0methyl)- 1,4-benz0di0xan In the same manner as set forth in Example II, a mixture of 9.2 g. of Z-chloromethyl-l,4 benzodioxan and 18.3 g. of 2-aminomethyl-6-methylpyridine was heated 6 hours at 135-141 C. and left overnight at room temperature.

Distillation of the crude products gave 11.8 g. (87.4%) of 2-(2-(6-methylpyridyl)-methylaminomethyl)-l,4-benzodioxan boiling at 160.0165.5/0.09 mm., n 1.5727. Treatment of the base with 6 N hydrochloric acid gave 12.4 g. of 2-(2-(6-methylpyridyl)methylaminomethyl)-1, 4-benzodioxan dihydrochloride as short White needles, melting at 142145 (from methanol-ethyl ether).

Analysis. Calculated for C H NO .2HCl: C, 55.98%; H, 5.87%; N, 8.16%. Found: C, 55.59%; H, 6.15%; N, 8.02%.

EXAMPLE VI 2-( B- (N -m0rph0lin0) ethylam inomethyl ,4-benz0di0xan In the same manner as set forth in Example II, a mixture of 9.2 g. of 2-chloromethyl-1,4-benzodioxan and 19.5 g. of N-(fl-aminoethyhmorpholine was heated 5.5 hours at -138 C. in an oil bath and left overnight at room temperature. Distillation of the crude basic fraction gave 10.6 g. (76.2%) of 2-(B-(N-morpholino)ethylaminornethyl)-1,4-benzodioxan as a colourless liquid boiling at 139- 164 C./0.020.2 mm. pressure, rr 1.5380. Treatment of the free base with 6 N hydrochloric acid gave 12.4 g. of Z-(B-(N-morpholino)ethylaminornethyl) 1,4 benzodioxan dihydrochloride as White powder melting at 222- 227 C.

Analysis. Calculated for C H N O 2HC1: C, 51.28%; H, 6.88%; N, 7.97%. .Found: C, 51.61%; H, 7.12%; N, 7.75%.

EXAMPLE VII 2-( -(N-morpholino)propylaminomethyl) 1 ,4-benzodioxan In the same manner as set forth in Example H, a mixture of 9.2 g. of 2-chloromethyl-1,4-benzodioxan and 21.6 g. of N-(' -aminopropybmorpholine was heated 7.5 hours at 125-130 C. and left overnight at room temperature. The crude basic fraction was distilled in vacuo to give 11.2 g. (76.7%) 2-( -(N-morpholino)propylaminomethyl)-1,4-benzodioxan as a colourless viscous liquid boiling at 158/0.0350.04 mm. 11 1.5349. Treatment of the free base with 6 N hydrochloric acid gave 12.7 g. of 2-( (N-morpholino )propylaminomethyD-1,4-benzodioxan dihydrochloride as white granules melting at 221225 C.

Analysis. Calculated for C H N O 2HCl: C, 52.60%; H, 7.17%; N, 7.67%. Found: C, 52.92%; H, 7.40%; N, 7.48%.

EXAMPLE VIII 2-(3-pyridylmethylaminomethyl) -6(7)methyl- 1 ,4-benz0di0xan In the same manner as set forth in Example II, a mixture of 9.93 g. of 2-chloromethyl-6(7)-methyl-1,4-benzodioxan and 16.2 g. of 3-picoly1amine was heated 6 hours at 118126 C. and left overnight at room temperature. Distillation of the crude basic fraction in vacuo gave 7.7 g. of 2-(3-pyridylmethylaminomethyl)-6(7)-methyl-1,4- benzodioxan as a pale yellow viscous liquid boiling at 171- 178/0.18 mm. n 1.5757. Treatment of the free base with 6 N hydrochloric acid gave 2-(3-pyridylmethylaminomethyl) 6(7) methyl-1,4-benzodioxan dihydrochlon'de melting at 137142 C.

7 Analysis. Calculated for C H N O 2HCl: C, 55.98%; H, 5.87%; N, 8.16%. Found: C, 55.68%; H, 6.18%; N, 8.09%.

EXAMPLE IX 2- (3 -pyridylmethylaminomethyl -6 7 -ch loro- 1,4-benzodioxan In the same manner as set forth in Example II, a mixture of 10.9 g. of 2-chloromethyl-6(7)-chloro-1,4-benzodioXan and 16.2 g. of 3-picolylamine was heated 7 hours at 123-129" C. and left overnight at room temperature. Distillation of the crude basic fraction in vacuo gave 8.2 g. (56.4%) 2 (3 pyridylmethylaminomethyl)-6(7)- chloro-1,4-benzodioxan as a yellow viscous liquid boiling at 175-194/0.1-0.13 mm., n 1.5883. Treatment of the base with 6 N hydrochloric acid gave 2-(3-pyridylmethylaminomethyl)-6(7)-chloro 1,4 benzodioxan dihydrochloride as white flakes melting at 144150 C.

Analysis. Calculated for C H ClN O- 2HCl: N, 7.70%. Found: N, 7.64%.

EXAMPLE X 2 (3 -(S-pyridylmethylaminomethyl) -5-methyl-8- isopropyl-I ,4-benzdi0xan In the same manner as set forth in Example II, a mixture of 12.1 g. of 2(3)-chloromethyl-5-methyl-8-isopropy1-1,4-benzodioxan and 16.2 g. of 3-picolylamine was heated 6.5 hours at l27136 C. in an oil bath and left overnight at room temperature. Distillation of the crude basic fraction in vacuo gave 6.7 g. (42.7%) of 2(3 (3 pyridylmethyl-aminomethyl) 5 methyl 8 isopropyl-1,4-benzodioxan pale yellow liquid boiling at 185-192/0.150.2 mm. n 1.5611. Treatment of the distillate with 6 N hydrochloric acid gave 2(3)-(3pyridylmethylaminomethyl) 5 methyl 8 isopropyl- 1,4-benzodioxan dihydrochloride as pale yellow crystals melting at 142-151 C.

Analysis.Calculated for 59.22%; H, 6.80%; N, 7.27%. 6.90%; N, 6.92%.

EXAMPLE XI 2-( -(N-morpholino)propylaminomethyl) -6(7)- ch loro-I ,4-benz0di0xan In the same manner as set forth in Example H, a mixture of 6.57 g. of 2chloromethyl-6(7)-chloro-l,4-benzodioxan and 13.0 g. of N-('y-aminopropyDmorpholine was heated 6 hours at 141-157 C. in an oil bath and left over the weekend at room temperature. Much coloration occurred during this period. The crude basic fraction was distilled in vacuo to give 8.1 g. (82.6%) of 2 ('y (N-morpholino)-pr0pylaminomethyl) 6(7)-chloro-1,4-benzodioxan as a colourless liquid boiling at 158- l86/0.06 mm., n 1.5420. The product treated with hydrochloric acid as described above gave 2-('y-(N-mor-. pholino)propylaminomethyl) 6(7)chloro 1,4 benzo- C19H24N202 C, Found: C, 59.04%; H,

EXAMPLE XII 2 (3 ('y (N-morpholino) propylaminomethyl) -5- methyl-8-isopr0pyl-I,4-benzodi0xan o OH NHCH CH CH N o CH3 CH3 In the same manner as set forth in Example II, a mixture of 7.25 g. of 2(3)-chloromethyl-5-methyl-8-isopropyl-1,4-benzodioxan and 13.0 g. of N-(w-aminopropyl)morpholine was heated 7.5 hours at 132157 C. in an oil bath and left overnight at room temperature. The crude basic fraction was distilled in vacuo to give 8.2 g. (78.8%) of 2(3)-('y-(N-morpholino)propylaminomethyl)-5-methyl-8-isopropyl-1,4-benzodioxan as a faintly yellow liquid boiling at 164.5-168.0/0.070.1 mm., n 1.5257. The distillate in anhydrous ethyl ether was treated with gaseous hydrogen chloride and recrystallized from methanol-ethyl ether to give 2(3)-(' -(N-morpholino) propylaminomethyl) 5 methyl 8 isopropyl- 1,4-benzodioxan dihydrochloride melting at 222-226".

Analysis.-Calculated for C H N O -2HC1: C, 57.00%; H, 8.13%; N, 6.64%. Found: C, 56.95%; H, 8.19%; N, 6.64%.

EXAMPLE XIII 2- ('y- (N-morpholino)propylaminomethyl) -6( 7) I methy l-1,4-benz0dioxan In the same manner as set forth in Example II, a mixture of 6.95 g. of 2-chloromethyl-6(7)-methyl-1,4-benzodioxan and 14.1 g. of N-(' -aminopropyDmorpholine was heated 5.5 hours at 135148 and left overnight at room temperature. The crude basic fraction was distilled to give 7.9 g. of 2-( -(N-morpholino)propylaminomethyl)- 6(7)-methyl-1,4-benzodioxan as a colourless liquid boiling at I53.160/0.09 mm., n 1.5325. The distillate in anhydrous ether was treated with dry hydrogen chloride and the precipitate recrystallized from methanolethyl ether to give 2-('y-(N-morpholino)propylaminomethyl)-6(7 )-methyl 1,4 benzodioxan dihydrochloride melting at 213.5218.5 C.

Analysis-Calculated for 53.82%; H, 7.43%; N, 7.38%. 7.64%; N, 7.04%.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as folows:

1. 1,4-benzodioxan derivatives of the general formula:

C17H23N2O3 C, Found: C, 53.40%; H,

wherein R and R are the same or diflerent and each represents a hydrogen or chlorine atom or a lower alkyl or lower alkoxy group, m represents zero or an integer from 1 to 5 and Z is morpholino or pyridyl having up to 1 lower alkyl substituent, joined to the group through a carbon or nitrogen atom and-acid addition salts thereof.

2. The compound according to claim 1 which is a hydrochloride addition salt.

3. A compound according to claim 1 wherein R is hydrogen and R is methyl.

4. 2-(2-pyridylamino)methyl-1,4-benzodioxan. 5. The monohydrochloride of the compound as claimed in claim 4.

6. 2-(3-pyridylamino)methyl-1,4-benzodioxan. 7. 2-(4-pyridylamino)methyl-1,4-benzodioxan. 8. 2 (2 pyridylamino)methy1 8 methoxy 1,4- benzodioxan.

9. 2-(3-pyridylarnino)methyl 8-methoxy-1,4-benzodioxan.

10. 2-(4-pyridylamino) methyl-S-methoxy-1,4-benzodioxan.

11. 2-(3-pyridylmethylaminomethyl)-1,4-benzodioxan. 12. 2-(4-pyridylmethylaminomethyl)-1,4-benzodioxan. 13. 2-(2-pyridylmethylaminomethyl)-1,4-benzodioxan. 14. 2 (2 (6 methylpyridyl)methylaminomethyl)- 1,4-benzodioxan.

15. 2 (p (N morpholino)ethylaminomethyl) 1,4- benzodioxan.

16. 2 (N-morpholino)propylaminomethyl)-1,4- benzodioxan.

17. 2 (3 pyridylmethylaminomethyl)-methy1 1,4- benzodioxan.

18. 2 (3 pyridylmethylaminomethyl) chloro 1,4- benzodioxan.

19. 2 (3 pyridylmethylaminomethyl) 5 methyl- 8-isopropyl-1,4-benzodioxan.

20. 2 ('y (N morpholino)propylaminomethyl)- chloro-lA-benzodioxan.

21. 2 ('y (N morpholino)propylaminomethy1) 5- methyl-S-isopropyl-1,4-benzodioxan.

22. 2 ('y (N morpholino)propylaminomethyl)- methyl-1,4-benzodioxan.

No references cited.

ALEX MAZEL, Primary Examiner.

HENRY R. IILES, Examiner.

R. J. GALLAGHER, Assistant Examiner. 

1. 1,4-BENZODIOXAN DERIVATIVES OF THE GENERAL FORMULA: 